Curr Hypertens Rep (2014) 16:477

DOI 10.1007/s11906-014-0477-1

HYPERTENSION AND THE KIDNEY (RM CAREY, SECTION EDITOR)

Renal Generation of Angiotensin II

and the Pathogenesis of Hypertension
Jorge F. Giani & Tea Janjulia & Brian Taylor & Ellen A. Bernstein & Kandarp Shah &
Xiao Z. Shen & Alicia A. McDonough & Kenneth E. Bernstein &
Romer A. Gonzalez-Villalobos

Published online: 6 August 2014

# Springer Science+Business Media New York 2014

Abstract The existence of a complete and functional reninangiotensin system along the nephron is widely recognized.
However, its precise role in blood pressure control and, by
extension, hypertension is still uncertain. While most investigators agree that overexpressing RAS components along the
nephron results in hypertension, two important issues remain:
whether the local RAS works as a separate entity or represents
an extension of the systemic RAS and whether locally generated angiotensin II has specific renal effects on blood pressure
that are distinct from systemic angiotensin II. This review
addresses these issues while emphasizing the unique role of
local angiotensin II in the response of the kidney to hypertensive stimuli and the induction of hypertension.

reading this review (in about 1 h), your kidneys will have
filtered the entirety of your plasma at least twice. Most of the
filtered volume is reclaimed because of the powerful sodium
and water retention capacity of the renal tubules and the
actions of the octapeptide angiotensin II. Thus, it is not surprising that angiotensin II can be produced locally within the
kidneys because of the activity of a complete reninangiotensin system (RAS) expressed along the nephron. In
fact, the renal RAS can play an important role in disease. This
review will discuss the evidence showing that the renal RAS is
pathologically activated by renal injury and inflammation and
that this activation represents a powerful mechanism to generate hypertension.

Keywords ACE . hypertension . kidney . RAS

Expression of RAS Components Along the Nephron Large

amounts of angiotensinogen accumulate in the proximal tubular
epithelium. Because this angiotensinogen is excreted into the
tubular lumen and in the urine, many investigators believe that
it can be cleaved by tubular renin and ACE to form angiotensin
II [13]. Support for this concept is provided by multiple
experiments showing that transgenic mice overexpressing human, rat or mouse angiotensinogen in proximal tubular epithelium develop hypertension and renal injury with no apparent
alterations of the systemic RAS [46]. The source of proximal
tubule angiotensinogen is still a point of contention. Recently,
Matsusaka et al. demonstrated that liver angiotensinogen is the
main source of angiotensinogen under basal conditions, at least
in mice [7]. However, their observation does not explain the
increases of angiotensinogen mRNA in kidneys from angiotensin II infused animals [8, 9]. As it stands today, it appears that
the angiotensinogen in segments 1 and 2 of the proximal tubule
is of systemic origin, while the angiotensinogen in segment 3 is
produced locally. Regardless of the source, an increased urinary
angiotensinogen excretion correlates with increases in renal
angiotensin II content [10]. The former observation serves as
the basis for clinical studies exploring urinary angiotensinogen

Introduction
The human kidney filters approximately 180 l of plasma every
day, the equivalent to 60 times the whole plasma volume of a
normal individual. Said another way, by the time you finish
This article is part of the Topical Collection on Hypertension and the
Kidney
J. F. Giani : T. Janjulia : B. Taylor : E. A. Bernstein : K. Shah :
X. Z. Shen : K. E. Bernstein : R. A. Gonzalez-Villalobos
Departments of Biomedical Sciences and Pathology and Laboratory
Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
A. A. McDonough
Department of Cell and Neurobiology, Keck School of Medicine,
University of Southern California, Los Angeles, CA, USA
R. A. Gonzalez-Villalobos (*)
Pfizer, DSRD CoE, 274 Eastern Point Road, MS 8274-1245, Groton,
CT 06340, USA
e-mail: romer.gonzalezvillalobos@pfizer.com

477, Page 2 of 5

excretion in humans. Multiple studies show that patients with

hypertension and several forms of renal disease display increased urinary angiotensinogen when compared to normal
subjects [11].
Tubular renin has at least three sources: systemic (i.e.,
juxtaglomerular) renin can be filtered. Renin can also be
produced, although in small quantities, by proximal tubule
cells and [12]; renin is also abundantly expressed in the distal
nephron, mainly by connecting tubules and collecting ducts
[1]. Multiple studies by Prieto-Carrasquero demonstrate that
distal renin expression is augmented in several forms of experimental hypertension, even in conditions when there is
substantial plasma renin suppression [13]. Recently, it was
shown that overexpressing collecting duct renin causes hypertension in mice [14]. Angiotensin-converting enzyme (ACE)
is expressed in multiple cell types within the kidney [15].
However, by far the site of highest expression is the brush
border of the proximal tubule. ACE expression has also been
detected in the distal nephron, although whether the source of
distal ACE activity is local production or absorbed proximal
tubule ACE is not clear. What is important is that ACE activity
is detectable throughout the nephron and in the urine [16].
Finally, AT1 receptors are ubiquitously expressed along the
nephron, although particularly high concentrations are found
in the thick ascending limb [17].
The Renal RAS and the Response to Local Parenchymal
Injury Experiments in Goldblatt and angiotensin II-infused
animals showed that renal angiotensin II levels are much
higher than those in the systemic circulation and subject to
local independent regulation [18]. This raised the question of
whether there was local angiotensin II production during
hypertension, even in high plasma angiotensin II states. Unequivocal evidence in favor of this hypothesis was provided
by experiments in rats infused with Val5-angiotensin II, an
isoform of angiotensin II separable from endogenous angiotensin II (Ile5-angiotensin II) by high-performance liquid chromatography [19]. These studies demonstrated that chronic
Val5-angiotensin II (exogenous angiotensin II) infusion induced renal Ile5-angiotensin II (endogenous angiotensin II)
synthesis. In another study, the increase in renal angiotensin II
content normally observed in angiotensin II-infused mice was
significantly reduced by concomitant treatment with an ACE
inhibitor [20]. Thus, several lines of evidence indicate that
local synthesis is an important contributor to the local pool of
angiotensin II in hypertensive states.
Why does the kidney respond to increases in plasma angiotensin II with local angiotensin II production? While the
idea of a feed-forward mechanism is not the prevailing view of
the RAS, the renal expression of several of its components,
namely tubular angiotensinogen, ACE, tubular renin, and the
AT1receptor, is either augmented or sustained during several
forms of experimental and human hypertension [21]. For

Curr Hypertens Rep (2014) 16:477

instance, renal RAS upregulation is well documented in the

hypertension induced by angiotensin II infusion and also by
nitric oxide synthesis inhibition [22, 23]. One hypothesis to
explain this is that renal RAS activation is an alarm response
and not a physiological process. For instance, in vitro studies
demonstrate that the proximal tubule angiotensinogen gene is
activated by several proinflammatory cytokines, including IL6 and IFN- [2427]. These cytokines can act independently
or synergistically with other factors, including angiotensin II,
high glucose, and reactive oxygen species to upregulate
angiotensinogen expression and secretion into the bathing
media. Although angiotensinogen is the best understood example, reports indicate that, at least in rodents, ACE and
tubular renin expression are also upregulated in many conditions associated with renal parenchymal injury. Another suggestion is that inflammatory cells express RAS components
and therefore, in conditions of renal inflammation, can become a separate source of local angiotensin II [28, 29].
The Specific Effects of Renal Angiotensin II Experiments in
the 1970s and 1980s showed that direct application of angiotensin I or RAS blockers (ACE inhibitors or AT1 receptor
blockers) into the renal artery led to acute changes in the
glomerular filtration rate (GFR) and sodium excretion
[3033]. The importance of this pioneering work was summarized elsewhere [34]. Here we focus on experiments in
gene-targeted mice as an important strategy to analyze the
exact effects of renal angiotensin II. For instance, our laboratory exploited the well-established fact that ACE is the main
source angiotensin II in renal tissues [35]. Specifically, we
analyzed the renal response of ACE gene-targeted mice to
hypertensive stimuli. One experiment was performed in mice
termed ACE 9/9 in which ACE expression is strictly limited to
renal tubular epithelium [18]. When exposed to chronic angiotensin I infusion, ACE 9/9 mice showed increased levels of
renal angiotensin II and urinary angiotensin II excretion. More
significantly, these mice developed hypertension similar in
magnitude to that observed in equally treated wild-type littermates. This experiment showed that renal tubular epithelial
ACE has the unique ability to increase the local concentration
and urinary excretion of angiotensin II and to induce hypertension even in the total absence of ACE and angiotensin II in
extra-renal tissues [18].
To verify this hypothesis, separate experiments studied ACE
3/3 and ACE 10/10 mice. In the ACE 3/3 mouse, ACE expression is restricted mostly to hepatocytes [36]. ACE 10/10 mice are
an inbred line that expresses ACE exclusively in
myelomonocytic cells [37]; these animals have essentially no
renal ACE. Both mouse strains have normal circulating levels of
ACE. They also have normal blood pressure and normal baseline
renal morphology and function. Remarkably, the absence of
renal ACE in the ACE 10/10 and ACE 3/3 mice significantly
reduced the hypertension in response to angiotensin II infusion (a

Curr Hypertens Rep (2014) 16:477

high serum angiotensin II model) or to reduced nitric oxide

production (a low serum angiotensin II model) [38, 39].
To better understand the effects of renal angiotensin II on
kidney function, we measured sodium and urine output of wildtype and mice lacking renal ACE (ACE 10/10 mice) during
angiotensin II infusion [38]. This approach clamped circulating angiotensin II to similar elevated levels. Angiotensin II
infusion caused a transient reduction of sodium and urine
output in wild-type mice that returned to pre-infusion levels
after 48 h. These changes were substantially blunted in the ACE
10/10 mice. After 3 days of infusion, sodium and urine outputs
were similar in both groups. However, in wild-type mice,
sodium balance was attained at the expense of hypertension,
consistent with a major shift in the pressure-natriuresis relationship. Importantly, the absence of hypertension in ACE 10/10
mice implies that the lack of kidney ACE prevents angiotensin
II infusion from shifting the pressure-natriuresis relationship, a
major mechanism in establishing hypertension according to
Guytons kidney-fluids hypothesis [39].
Similar observations were made during hypertension induced
by nitric oxide synthase inhibition with L-NAME (L-NAME
induced hypertension) [40]. In this model, the protection against
the hypertension by the lack of renal ACE was even more
pronounced; while wild-type mice became hypertensive, the
Fig. 1 The absence of renal ACE
derived-angiotensin II formation
prevents the hypertension and
sodium retention induced by
systemic nitric oxide synthesis
inhibition. Wild-type and mice
lacking renal ACE (ACE 10/10)
were given L-NAME, a nitric
oxide synthesis inhibitor, in the
drinking water (5 mg/10 ml).
Values represent meanSEM;
N=610, ***P<0.001 versus
wild-type mice. Data were
published elsewhere [38]

Page 3 of 5, 477

blood pressure of ACE 10/10 mice remained essentially unchanged (Fig. 1). Sodium balance studies reveal that in LNAME treated wild-type mice it was restored at the expense of
hypertension. In sharp contrast, ACE 10/10 mice showed an
enhanced natriuretic response that allowed them to maintain
normal blood pressure values (Fig. 1). As a whole, these observations support a very novel concept, namely that shifting of the
renal pressurenatriuresis relationship toward hypertension ultimately depends on renal ACE and the angiotensin II produced
locally in the kidney, and not on systemic effects of angiotensin II.
In theory, the renal sodium dysregulation facilitated by the
renal ACE/angiotensin II pathway can be induced by changes
in glomerular filtration rate (GFR) and/or sodium reabsorption. With this in mind, the GFR response to L-NAME was
studied in conscious, unrestrained wild-type and ACE 10/10
mice via a transcutaneous method [41]. Whereas wild-type
mice responded to L-NAME with acute reductions in GFR,
the GFR of equally treated ACE 10/10 mice remained unchanged. The explanation for this observation is not clear, but
it suggests that the renal ACE/angiotensin II pathway is also
important in modulating renal hemodynamic responses to
hypertensive stimuli.
The effects of the renal ACE/angiotensin II pathway on
sodium transport have also been explored. An extensive

477, Page 4 of 5

expression analysis included the Na+/H+ exchanger (NHE3),

loop of Henle Na+/K+/2Clco-transporter 2 (NKCC2), distal
tubule NaCl co-transporter (NCC), epithelial sodium channel
(ENaC), anion exchangers pendrin and NDBCE, and
Na+/K+ATPase, among others. In both the L-NAME hypertension and angiotensin II infusion models, the presence of kidney
ACE was associated with increased sodium transport. The
most striking differences between wild-type and mutant mice
were observed in response to angiotensin II infusion, where the
presence of kidney ACE facilitated substantial increases in abundance, phosphorylation, and/or processing of NKCC2, NCC,
ENaC, and pendrin in the loop of Henle and the distal nephron.
In the specific case of NKCC2 and NCC, the two transporters
with the most significant changes, increased abundance and/or
phosphorylation were consistent with increased in vivo transporter activation (as measured by the response to specific blockers).
Remarkably, the described changes were either totally absent or
substantially attenuated in equivalently treated ACE 10/10 mice.
Hence, while it is well established that angiotensin II regulates
NKCC2, NCC, ENaC, and pendrin, a major conclusion from
these studies is the dominant effect of locally generated angiotensin II in regulating sodium transport along the nephron. Thus,
the evidence suggests that the renal ACE/angiotensin II pathway
serves as a master switch for sodium transport along the nephron.

Curr Hypertens Rep (2014) 16:477

Xiao Z. Shen has received a grant from the American
Heart Association.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.

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Conclusions
Emerging evidence supports an important and obligatory role
of angiotensin II generated within the kidney in hypertension.
Experiments in gene-targeted mice reveal the importance of
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Acknowledgement The authors are supported by NIH grants

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Compliance with Ethics Guidelines

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Conflict of Interest Jorge F. Giani, Tea Janjulia, Brian Taylor, Ellen

Bernstein, Kandarp Shah, Alicia A. McDonough, Kenneth E. Bernstein,
and Romer A. Gonzalez-Villalobos declare that they have no conflict of
interest.

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